Improved methods for the identification of physiologically important protein-protein interactions are in great demand. We have devised a novel system which allows the selection of protein or peptide ligands of a protein of interest from complex mixtures by virtue of their ability to facilitate the replication of their own genes. A cDNA library is cloned for filamentous phage display on non-infectious phage. The protein of interest, or 'bait' protein, is expressed as a fusion with an infectivity-conferring fragment of the minor phage coat protein, which is secreted into the periplasmic space of E. coli. Co-expression of the cDNA library and the 'bait' protein construct in the same cell will result in the production of infectious phage when and only when the cDNA translation product has significant affinity for the 'bait' protein. "Bait' protein binders, with their genes encoded in the phage, can then be recovered by simple plaque assay, or they can be selectively amplified by growth in suspension. This method has important advantages over comparable methods such as the two-hybrid system. It should be useful for extracellular interactions and should produce lower false positive backgrounds. PROPOSED COMMERCIAL APPLICATION: The identification of all interacting proteins in complex physiological processes such as the immune response is essential for the ultimate elucidation of the molecular mechanisms by which such processes are effected and controlled. Only with such knowledge can truly safe and effective therapies be developed.